Different effects of the hypolipidemic drugs pravastatin and lovastatin on the cholesterol biosynthesis of the human ocular lens in organ culture and on the cholesterol content of the rat lens in vivo

Vries, A.C.J. de; Cohen, Louis

doi:10.1016/0005-2760(93)90218-x

Cited by 21 publications

(9 citation statements)

References 22 publications

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“…There are several studies indicating that simvastatin but not pravastatin is able to penetrate the BBB (de Vries and Cohen, 1993;Saheki et al, 1994), causing CNS side effects such as sleep disturbances. The ability to cross the BBB is thought to be caused by the difference in lipophilicity.…”

Section: Discussionmentioning

confidence: 99%

Brain Cholesterol Synthesis in Mice Is Affected by High Dose of Simvastatin but Not of Pravastatin

Thelen

Rentsch

Gutteck

et al. 2005

J Pharmacol Exp Ther

135

122

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On a global scale, there is an increasing tendency for a more aggressive treatment of hypercholesterolemia. Minor effects of statins on brain cholesterol metabolism have been reported in some in vivo animal studies, and it seems that this is due to a local effect of the drug. We treated male mice of the inbred strain C57/BL6 with a high daily dose of lipophilic simvastatin (100 mg/kg b.wt.) or hydrophilic pravastatin (200 mg/kg b.wt.) or vehicle (controls) by oral gavage for 3 days. To compare the impact of both statins on brain cholesterol synthesis and degradation, levels of cholesterol, its precursor lathosterol, and its brain metabolite 24(S)-hydroxycholesterol as well as statin concentrations were determined in whole-brain lipid extracts using mass spectrometry. The expression of 3-hydroxy-3-methylglutaryl (HMG)-coenzyme A (CoA) reductase mRNA and of other target genes were evaluated using real-time reverse transcription-polymerase chain reaction. In addition, analysis of liver and serum samples was performed. Similar levels of simvastatin and pravastatin were detected in whole-brain homogenates. Cholesterol contents in the brain, liver, and serum were not affected by high-dose statin treatment. Whereas brain cholesterol precursor levels were reduced in simvastatin-treated animals only, no effect was observed on the formation of the brain cholesterol metabolite, 24(S)-hydroxycholesterol. Polymerase chain reaction analysis revealed that mRNA expression of HMG-CoA reductase and ATP-binding cassette transporter A1 in the brain was significantly up-regulated in simvastatintreated animals compared with pravastatin-treated or control animals. We conclude that, under the present experimental conditions, brain cholesterol synthesis is significantly affected by short-term treatment with high doses of lipophilic simvastatin, whereas whole-brain cholesterol turnover is not disturbed.

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Section: Discussionmentioning

confidence: 99%

Brain Cholesterol Synthesis in Mice Is Affected by High Dose of Simvastatin but Not of Pravastatin

Thelen

Rentsch

Gutteck

et al. 2005

J Pharmacol Exp Ther

135

122

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“…It is not clear if the high Chol content and the appearance of CBDs and/or Chol crystals are harmful or beneficial to lens function, especially lens transparency (Borchman et al 1996; Jacob et al 1999; Mason et al 2003; Tulenko et al 1998). The significance of cholesterol in the eye lens is emphasized by observations that inherited defects in cholesterol metabolism enzymes and use of cholesterol-biosynthesis-inhibiting drugs cause cataract formation in animals and humans (Borchman et al 1989; Cenedella 1996; de Vries and Cohen 1993; Kirby 1967; Mosley et al 1989). These earlier observations were recently confirmed by retrospective cohort studies comparing the risk of development of cataracts between statin users and non-users which showed that the risk of cataract development was increased among statin users (Lai et al 2013; Leuschen et al 2013; Machan et al 2012).…”

Section: Introductionmentioning

confidence: 99%

Properties of membranes derived from the total lipids extracted from clear and cataractous lenses of 61–70-year-old human donors

et al. 2014

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Human lens-lipid membranes prepared from the total lipids extracted from clear and cataractous lens cortexes and nuclei of 61–70-year-old donors by use of a rapid solvent-exchange method were investigated. The measured cholesterol-to-phospholipid (Chol/PL) molar ratio in these membranes was 1.8 and 4.4 for cortex and nucleus of clear lenses, respectively, and 1.14 and 1.45 for cataractous lenses. Properties and organization of the lipid bilayer were investigated by use of electron paramagnetic resonance spin-labeling methods. Formation of Chol crystals was confirmed by use of differential scanning calorimetry. Pure cholesterol bilayer domains (CBDs) were formed in all the membranes investigated. It was shown that in clear lens membranes of the nucleus, Chol exists in three different environments: (1) dispersed in phospholipid bilayers (PCDs), (2) in CBDs, and (3) in Chol crystals. In clear lens membranes of the cortex, and in cortical and nuclear cataractous lens membranes, Chol crystals were not detected, because of the lower Chol content. Profiles of membrane properties (alkyl-chain order, fluidity, oxygen transport, and hydrophobicity) across the PCD were very similar for clear and cataractous membranes. Profiles of the oxygen transport parameter across the CBD were, however, different for cortical clear and cataractous membranes—the amount and size of CBDs was less in cataractous membranes. These results suggest that high Chol content, formation of CBDs, and formation of Chol crystals should not be regarded as major predispositions for the development of age-related cataracts.

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“…Number of papers have described the effect of hypolipidemic drugs on levels of cholesterol and triacylglycerols in serum (Illingworth and Tobert 1994) and on the liver lipid metabolism (Alegret et al 1998), but there are only a few studies focused on other tissues e.g. skin (Wolf et al 1999), vascular wall (Bellosta et al 1998) and eye-lens (De Vries and Cohen 1993).…”

mentioning

confidence: 99%

Hypolipidemic Drugs Can Change the Composition of Rat Brain Lipids

Vecka

Tvrzická

Staňková

et al. 2004

Tohoku J. Exp. Med.

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Hypolipidemic drugs are potent serum cholesterol lowering agents used for prevention of coronary heart disease. In addition to their cholesterol lowering effect, these drugs exhibit both pleiotropic beneficial and various neurological side effects. Therefore, we analysed effect of the hypolipidemic drugs, fenofibrate and statins, on membrane lipid composition in the rat brain tissue. Male Wistar rats were given 0.1 mg of fenofibrate, lovastatin, pravastatin, fluvastatin or placebo (control) once daily for six weeks. In rats treated with lovastatin or pravastatin, decreased cholesterol and increased ceramide monohexoside contents in the brain tissue were observed in comparison with control. Treatment with fluvastatin or lovastatin resulted in increased sphingomyelin and decreased diphosphatidylglycerol contents. The most important changes in the fatty acid profile were observed in ceramide monohexosides; treatment with fluvastatin decreased the content of saturated and increased the content of polyunsaturated fatty acids. Fenofibrate treatment led to decreased content of saturated fatty acids in phosphatidylethanolamines. In conclusion, statin treatment resulted in the decreased content of cholesterol and diphosphatidylglycerol associated with the increased content of sphingolipids in the rat brain tissue. As cholesterol and sphingolipids are important components of brain membranes, the observed alterations in the composition brain lipids might be involved in genesis of neurological and mental symptoms following statin therapy.statin; fibrate; brain; lipids; fatty acid

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Different effects of the hypolipidemic drugs pravastatin and lovastatin on the cholesterol biosynthesis of the human ocular lens in organ culture and on the cholesterol content of the rat lens in vivo

Cited by 21 publications

References 22 publications

Brain Cholesterol Synthesis in Mice Is Affected by High Dose of Simvastatin but Not of Pravastatin

Brain Cholesterol Synthesis in Mice Is Affected by High Dose of Simvastatin but Not of Pravastatin

Properties of membranes derived from the total lipids extracted from clear and cataractous lenses of 61–70-year-old human donors

Hypolipidemic Drugs Can Change the Composition of Rat Brain Lipids

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